The present invention relates to the use of compressed CO2 in chemical reactions. More particularly, it relates to homogeneous catalysis in compressed CO2, e.g. metal-catalysed reactions, and also to the synthesis of cross-linked polymers in CO2.
Metal-catalysed processes are extremely common in the formation of organic molecules, in particular pharmaceuticals, agrochemicals, flavours, fragrances and other consumer products. The use of a coordinating ligand, in such transformations, allows control of such variables as reaction rates, asymmetric induction, solubility, functional group specificity, product distribution and the yield of the process.
Metal-catalysed processes are typically conducted in conventional organic solvents (VOCsxe2x80x94volatile organic compounds). However, these materials have several drawbacks associated with their use. VOCs can be expensive, toxic (benzene, chlorofluorocarbons, acetonitrile), flammable (diethyl ether), restricted in availability (CFCs), difficult to process (solvent residues) and have associated disposavrecycling problems.
Compressed carbon dioxide is an attractive solvent for the preparation of organic molecules because it is inexpensive, non-toxic, and non-flammable. Unlike conventional liquid solvents, compressed CO2 is highly compressible and the density (and therefore solvent properties) can be tuned over a wide range by varying the pressure. Moreover, compressed CO2 reverts to the gaseous state upon depressurisation, greatly simplifying the separation of solvent from solute(s) and thereby reducing solvent residues in the products.
The metal-catalysed formation of organic molecules, in compressed CO2, has been very limited: hydrogenation [Burk et al, J. Am. Chem. Soc. (1995) 117, 8277; Jessop et al, Nature (1994) 368, 231], hydroformylation [Kainz et al, Angew. Chem. Int. Ed. Engl. (1997) 36, 1628] and others [Furstner et al, Angew. Chem. Int. Ed. Engl. (1997) 36, 2466] have been reported.
WO-A-9601851 discloses polymerisation processes, including olefin metathesis in CO2. A fluorinated dispersing agent may be used.
Cross-linked polymer resins are useful in a wide range of applications, including solid-phase synthesis, combinatorial chemistry, polymer-supported reagents, molecular imprinting, size-exclusion chomatography, ion-exchange resins, medical diagnostics, and the controlled release of drugs. In all of these various applications, it is often desirable to produce the cross-linked resins in the form of uniform microspheres. This is usually achieved by heterogeneous methods such as suspension, dispersion, or emulsion polymerisation [Arshady, Colloid Polym. Sci., (1992) 270, 717]. Typically, amphiphilic surfactants or stabilisers are used to prevent particle coalescence in these processes; however, residual surfactant on the particle surfaces may sometimes impair the performance properties of the resulting polymers. The formation of uniform cross-linked polymer microspheres has been achieved in the absence of surfactants; however, the solvents employed are often toxic (e.g., acetonitrile) [Li et al, J. Polym. Sci., Part A, Polym. Chem., 1993, 31, 3257] and/or expensive (e.g. perfluorocarbons) [Zhu, Macromolecules (1996) 29, 2813].
Supercritical carbon dioxide (scCO2) is an attractive solvent for polymer chemistry because it is inexpensive, non-toxic, and non-flammable [Canelas et al, Adv. Polym. Sci. (1997) 133, 103]. Unlike conventional liquid solvents, scCO2 is highly compressible and the density (and therefore solvent properties) can be tuned over a wide range by varying pressure. Moreover, scCO2 reverts to the gaseous state upon depressurisation, greatly simplifying the separation of solvent from solute(s). scCO2 has been used as a solvent medium for homogeneous polymerisations [DeSimone et al, Science (1992) 257, 945; and PCT/US93/01626] and heterogeneous precipitation polymerisations [Romack et al, Macromolecules (1995) 28, 912]. In many cases, the precipitation polymerisation of polymers which are insoluble in scCO2 occurs, to give low polymer yields and undefined, agglomerated polymer morphologies [Canelas et al, supra].
Polymeric surfactants or stabilisers have been developed which allow the synthesis of CO2-insoluble polymers in scCO2 in high yields by dispersion polymerisation [DeSimone et al, Science (1994) 265, 356; Canelas et al, Macromolecules (1997) 30, 5673; U.S. Pat. No. 5,679,737]. By using the appropriate surfactants or stabilisers, it was possible to generate these polymers as uniform microspheres. All of these examples relate to the polymerisation in scCO2 of monomers containing a single polymerisable functional group (e.g. styrene, methyl methacrylate, acrylic acid) and not bi- or multi-functional monomers of the type known to promote cross-linking in polymerisations (e.g. divinylbenzene (DVB), trimethylol propane trimethacrylate (TRM), ethylene glycol dimethacrylate (EGDMA)).
U.S. Pat. No. 4,748,220 discloses that cross-linked polymer particles were formed in liquid or supercritical CO2. The polymers were formed as pulverulent powders with primary particles in the size range 0.5-3 xcexcm; however, the particles were not formed as regular microspheres. The use of scCO2 to form cross-linked nanoporous polymer monoliths [U.S. Pat. No. 5,629,353] and microcellular cross-linked foams [U.S. Pat. Nos. 5,128,382; 4,748,220; 5,066,684] has also been described.
A first aspect of the present invention is based on the surprising observation that the incorporation of perfluorinated chains dramatically increases the solubility of ligand-metal complexes in compressed CO2, and enables metal-catalysed reactions to take place in a non-polar medium without chemical participation of the carbon dioxide. This improved solubility allows the ligand metal complexes to act as homogeneous catalysts. In particular, fluorinated phosphines are useful in palladium-catalysed processes. An application of particular value is where a reactant is immobilised on a material that swells in the presence of CO2.
A second aspect of the present invention is based on the surprising discovery that a range of cross-linked polymers can be formed using compressed CO2 as the polymerisation medium, and that the polymers can be isolated in high yields directly from the reaction vessel as dry, free-flowing powders, in the form of discrete, uniform microspheres. This may be done, depending on the reactants and conditions, with or without the use of added surfactants. The invention thus provides for the synthesis of a range of cross-linked copolymers in CO2 for a variety of potential applications, including molecular imprinting, solid-phase synthesis, combinatorial chemistry, polymer supported reagents, size-exclusion chomatography, and medical diagnostics.
The polymerisation route is simple, polymer yields are high, the solvent can be easily separated from the products, and the procedure allows the formation of uniform polymer microspheres with diameters in the range 1-5 xcexcm by suspension or precipitation polymerisation, from styrenic monomers, without the use of any surfactants or stabilisers. When surfactants are used, smaller particles with controlled sizes of less than 0.5 xcexcm diameter can be formed by emulsion polymerisation.
The first aspect of this invention typically uses fluorinated phosphorus-derived ligands of the formula 
wherein X is selected from O, S and Se or may simply be an unshared pair of electrons. Preferably, X is O or S. Most preferably, is X is an unshared electron pair.
R1, R2 and R3 may each be any non-interfering group. Examples are alkyl, aryl, heteroaryl, alkoxy, aryloxy, heteroaryloxy, thioalkyl, thioaryl, thioheteroaryl, aminoalkyl (primary, secondary, tertiary), aminoaryl, imino.
Preferably, R1 or R2 carries a perfluorinated carbon chain or partially fluorinated carbon, siloxy or short polyether chain. The carbon chain is a substituent in its own right or a group within the chosen substituent. It is selected from chain length C1 to C40, preferably C4 to C8 and most preferably C6. It may be branched or linear. Typically, the perfluorinated part comprises at least 1, 2, 3, 4, 5 or more C atoms.
R1, R2 and R3 may be further modified by carrying another metal-chelating substituent such as a phosphine, nitrogen, oxygen or sulfur-based functionality or arsine.
The phosphorus in formula 1 may instead be arsenic.
For specific applications, one preference is for R1=R2=CH2CH2C6F13 and R3=Ph. The perfluorinated group is part of the substituent.
The use of fluorinated ligands increases the solubility of ligand-metal complexes in compressed CO2. It is also shown that solubility for a given complex is dependant upon the degree of fluorination. Metals that may show the effect of improved solubility with fluorinated ligands are Pd, Pt, Ni, Rh, Ru, Ir, Al, Mo, W, Re, Os, Hg, Pb, Au, Ag, Cr, Co, Mn, Mg, Zn, Fe, Zr, Ti having oxidation states in the range (0) to (8). Palladium (II), leading to a reactive palladium (0) species is preferred.
A range of catalyst concentrations may be employed in metal-catalysed processes. Typical concentrations are in the range of 0.01-50 mol % versus substrate, with preference for 1-10 mol %, specifically 1-5 mol % catalyst concentration.
The yield of product for a given process is dependant on the time of reaction, catalyst concentration, temperature and the identity of other reagents.
A range of reaction types may be conducted in compressed CO2 and fluorinated ligand-metal complexes are versatile catalysts in compressed CO2. Both intramolecular and intermolecular metal-catalysed processes may be conducted. Specific types of reactions that may be conducted using fluorinated ligand-metal complexes are hydrogenation, hydroboration, hydrosilylation, hydrocyanation, hydroformylation, allylic substitution, carbonylation, cross-coupling processes, cyclisation processes, conjugate addition, oxidation and epoxidation. Preferably, palladium-mediated carbon-carbon bond forming reactions take place. Most specifically, Heck [see Heck, xe2x80x9cPalladium Reagents in Organic Synthesisxe2x80x9d, Academic Press, Orlando. 1985], Suzuki [see Migaura et al, Syn. Commun. (1981) 11, 513]; Sonogashira [see Sonogashira et al, Tetrahedron. Lett. (1975) 4467] and Stille couplings are surprisingly effective in compressed CO2. This is surprising, because polar solvents are specifically preferred for the Heck reaction [see Spencer, J. Organomet. Chem. (1983) 258, 101]. Further, boronic acids of the type suitable for use in the Suzuki reaction are surprisingly soluble in CO2.
For the Heck reaction, it is particularly preferred to use an aryl iodide as the substrate. As the complex, palladium acetate is preferred since it is reactive, gives good yields and can be generated in situ.
An important advantage of this invention is the surprising ease of product isolation in comparison to conventional techniques. Improvements in product separation and purification using tandem supercritical fluid extraction (SFE) and supercritical fluid chromatography (SFC) are expected. Other advantages in this area of process development may include the use of the catalysts in solid-phase synthesis.
The process of this invention is particularly suited to the use of palladium-mediated coupling reactions in compressed CO2, in which there are one or more reactants supported on resins or dendrimers which undergo swelling by compressed CO2. This may accelerate reaction rates and enhance mass transport within the supported reactant.
The second aspect of this invention refers to the formation of cross-linked polymers in compressed CO2 (by way of example only xe2x80x9cscCO2xe2x80x9d may be discussed below) by the polymerisation of multi-functional monomers containing two or more polymerisable functional groups. Examples of such monomers are bi-/multi-functional styrene monomers, bi-/multi-functional methacrylate monomers, bi-/multi-functional acrylate monomers, bi-/multi-functional allyl ether monomers, bi-/multi-functional epoxide monomers, and bi-/multi-functional oxetane monomers. The most preferred monomers are divinylbenzene 1, ethylene glycol dimethacrylate 2, and trimethylol propane trimethacrylate 3 
It will be evident that the polymerisation process of the invention may utilise one or more monomers. There may be one or more monomers containing two or more polymerisable groups, optionally together with one or more of other copolymerisable monomers. The weight of the cross-linker with respect to total monomer weight is typically 2-100%, preferably 40-100%. Using more than 50% of a styrenic monomer such as DVB, and a concentration of monomers in CO2 of between 15 and 40 vol %, surfactant is unnecessary. If less reactive monomers, and therefore also a surfactant, are used, the monomer concentration in CO2 is less critical.
The cross-linked polymers can be isolated as dry, free-flowing powders, directly from the reactor. Since the solvent, CO2, reverts to a gas upon depressurisation, no solvent residues are left in the resulting cross-linked polymers, and the use of VOC solvents is avoided.
Under certain conditions, regular polymeric microspheres (1-5 xcexcM diameter) can be formed by suspension polymerisation in the absence of any added surfactants or stabilisers. In the presence of a surfactant, highly regular cross-linked microspheres ( less than 0.5 xcexcm diameter) can be formed by emulsion polymerisation in scCO2.
The polymerisation procedure works efficiently in scCO2 when thermal-free radical initiation is used, employing 2,2xe2x80x2-azobisisobutyronitrile (AlBN) at 65xc2x0 C. as the preferred initiator. Other free-radical initiators (either thermally or photochemically-decomposed) may be used, as may be cationic initiators, e.g. in the case of ring-opening polymerisations of oxirane/oxetane-based cross-linking monomers.
scCO2 is a useful and versatile solvent for the synthesis of cross-linked resins in the form of uniform microspheres with precise control of particle size and morphology. The ease of separation of solvent from solute is an important advantage. Other advantages may include the formation of macroporous cross-linked structures by swelling with scCO2, and the tuning of cross-linked particle size and morphology by the variation of CO2 pressure during polymerisation. A range of cross-linked copolymers may be generated, by copolymerisation of the cross-linker with comonomers which contain surface-active or derivatisable/reactive functional groups.
Preferred comonomers of this type contain alkyl, alkyl chloride, aryl fluoride, fluoroalkyl and carboxylic acid functional groups. Specific examples are: 
Other suitable comonomers contain poly(dimethyl siloxane) chains, low molecular weight poly(ethylene glycol) chains, perfluoropolyether chains, alkyl bromides, alkyl iodides, alcohols (alkyl and aryl), protected alcohols (alkyl and aryl), esters (alkyl and aryl), aldehydes (alkyl and aryl), amines (alkyl and aryl), amides (alkyl and aryl), crown ethers, porphyrins, fluorescent functional groups, radio-labelled functional groups, template groups for molecular imprinting, hygroscopic groups for the formation of superabsorbent polymers, functional groups for affinity chromatography, derivatisable functional groups for parallel synthesis on well-defined polymer beads, organic dyes, pharmaceutical molecules for controlled drug delivery, inorganic/organic reagents for organic synthesis, and transition metal/main group metal catalysts.
By way of example, cross-linked polymer microspheres incorporating a dispersed organic dye can be synthesised by this method. The polymer environment may contain functional groups of the type used in molecular imprinting (e.g. the carboxylic acid functionalities in a methacrylic acid comonomer). Cross-linked microspheres may incorporate other molecules, such as template molecules for molecular imprinting, pharmaceuticals for controlled release, biomolecules, fluorescent molecules, odour-releasing molecules (e.g. fragrances), rigid rod fluorophores, LED fluorescent emitters, and molecules with magnetic properties.
Any surfactant used in the invention should be soluble in CO2. The amount of surfactant that is used may be, for example, 0.25 to 5% w/w, preferably about 3% w/w, with respect to monomer.
A CO2-soluble, diblock copolymer surfactant has been synthesised by a modified screened anionic polymerisation (SAP) route [see Yong et al. Chem. Commun. (1997) 1811]. It has the formula 
The copolymer, which contains a CO2-soluble fluorinated segment and a methacrylate-based anchoring segment, was found to be highly soluble in scCO2. The use of this surfactant has been shown to lead to the formation of uniform cross-linked microspheres (diameter  less than 0.5 xcexcm) by emulsion polymerisation in scCO2. The most preferred surfactants are diblock copolymers prepared by screened anionic polymerisation consisting of a CO2-soluble poly(fluoro methacrylate) block and a CO2-insoluble poly(methyl methacrylate) anchoring block. Other surfactants that may be suitable use in the invention are fluorinated graft copolymers, siloxane-based graft copolymers, diblock copolymer surfactants consisting of a CO2-soluble poly(fluoro methacrylate) block and a CO2-insoluble poly(styrene) anchoring block, diblock copolymer surfactants consisting of a CO2-soluble poly(siloxane) block and a CO2-insoluble poly(methyl methacrylate) anchoring block, and diblock copolymer surfactants consisting of a CO2-soluble poly(siloxane) block and a CO2-insoluble poly(styrene) anchoring block.
Accordingly, cross-linked copolymers are synthesised in scCO2 and can be isolated directly from the reactor in the form of uniform microspherical particles both with and, unexpectedly, without the use of added surfactants.